Smyth M J, Kelly J M, Sutton V R, Davis J E, Browne K A, Sayers T J, Trapani J A
Cancer Immunology Division, Trescowthick Laboratories, Peter MacCallum Cancer Institute, Melbourne, Australia.
J Leukoc Biol. 2001 Jul;70(1):18-29.
Cytotoxic lymphocytes largely comprise CD8(+) cytotoxic T cells and natural killer cells and form the major defense of higher organisms against virus-infected and transformed cells. A key function of cytotoxic lymphocytes is to detect and eliminate potentially harmful cells by inducing them to undergo apoptosis. This is achieved through two principal pathways, both of which require direct but transient contact between the killer cell and its target. The first, involving ligation of TNF receptor-like molecules such as Fas/CD95 by their cognate ligands, results in mobilization of conventional, programmed cell-death pathways centered on activation of pro-apoptotic caspases. This review concentrates on the second pathway, in which the toxic contents of secretory vesicles of the cytotoxic lymphocyte are secreted toward the target cell, and some toxins penetrate into the target cell cytoplasm and nucleus. In addition to invoking a powerful stimulus to caspase activation, this "granule-exocytosis mechanism" provides a variety of additional strategies for overcoming inhibitors of the caspase cascade that may be elaborated by viruses. The key molecular players in this process are the pore-forming protein perforin and a family of granule-bound serine proteases or granzymes. The molecular functions of perforin and granzymes are under intense investigation in many laboratories including our own, and recent advances will be discussed. In addition, this review discusses the evidence pointing to the importance of perforin and granzyme function in pathophysiological situations as diverse as infection with intracellular pathogens, graft versus host disease, susceptibility to transplantable and spontaneous malignancies, lymphoid homeostasis, and the tendency to auto-immune diseases.
细胞毒性淋巴细胞主要由CD8(+)细胞毒性T细胞和自然杀伤细胞组成，是高等生物抵御病毒感染细胞和转化细胞的主要防线。细胞毒性淋巴细胞的一个关键功能是通过诱导潜在有害细胞凋亡来检测和清除它们。这是通过两条主要途径实现的，两条途径都需要杀伤细胞与其靶细胞之间直接但短暂的接触。第一条途径涉及TNF受体样分子（如Fas/CD95）与其同源配体的结合，导致以促凋亡半胱天冬酶激活为中心的传统程序性细胞死亡途径的动员。本综述集中于第二条途径，即细胞毒性淋巴细胞分泌囊泡的毒性内容物朝向靶细胞，一些毒素穿透进入靶细胞的细胞质和细胞核。除了引发对半胱天冬酶激活的强大刺激外，这种“颗粒胞吐机制”还提供了多种额外策略来克服病毒可能产生的半胱天冬酶级联反应抑制剂。这一过程中的关键分子是成孔蛋白穿孔素和颗粒结合丝氨酸蛋白酶家族或颗粒酶。包括我们自己实验室在内的许多实验室都在深入研究穿孔素和颗粒酶的分子功能，并将讨论最近的进展。此外，本综述还讨论了证据，这些证据表明穿孔素和颗粒酶功能在多种病理生理情况下的重要性，如细胞内病原体感染、移植物抗宿主病、对可移植和自发性恶性肿瘤的易感性、淋巴细胞稳态以及自身免疫性疾病的倾向。
